Antiphlogistic and anticoagulant condensed pyrimidine derivatives

15 g. of 1,6-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2a)pyrimidinium methylsulfate are heated in the mixture of 450 ml. of benzene and 50 g. of triethylamine and after cooling the mixture is allowed to stand overnight in a refrigerator. The precipitated crystals are filtered. The filtrate is evaporated. The obtained residue is recrystallized from ethanol and thus yellow 1,6-dimethyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained. Melting point: 171°-172° C.

Analysis: calculated: C 59.71%; H 6.83%; N 18.99%. found: C 59.85%; H 6.87%; N 19.03%.

50 g. of 1,6-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyridinium methylsulfate are dissolved in 150 ml. of water and the pH of the solution is adjusted to neutral by adding 13.9 g. of solid sodium bicarbonate and from the resulting 1,6-dimethyl-3-carbamoyl-9a-hydroxy-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)pyrimidine 1,6-dimethyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is formed by discharging water and the product is precipitated from the solution in the form of crystals.

After standing for 2 hours at room temperature the crystals are filtered, washed with water and dried. 26.5 g. of yellow crystals are obtained, melting point: 165°-171° C. The aqueous filtrate is shaken out with chloroform and the chloroform solution is evaporated and a further 1.8 g. of yellow crystals are obtained, melting point: 162°-168° C.

Total yield: 86%. The combined crystalline substance is recrystallized from ethanol and thus the melting point of the resulting 1,6-dimethyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is raised to 170°-172° C. There is no decrease in the melting point compared with the product of Example I.

15.3 g. of 1,6-dimethyl-3-(N-acetyl-carbamoyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyridinium methyl sulfate are dissolved in 50 ml. of water. The solution is neutralized with a 5% sodium carbonate solution and thus 1,6-dimethyl-3-(N-acetyl-carbamoyl)-9a-hydroxy-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)pyrimidine is formed which is converted to 1,6-dimethyl-3-(N-acetyl-carbamoyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine by discharge of water and it is precipitated from the aqueous solution. The precipitated yellow crystals are filtered, covered with water, and dried. 9.2 g. (86%) of the product is obtained, melting point: 182°-184° C. After recrystallization from ethanol the melting point of the resulting 1,6-dimethyl-3-(N-acethyl-carbamoyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-(1,2a)pyrimidine is 183°-185° C.

Analysis: calculated: C 59.30%; H 6.51%; N 15.96%. found: C 59.80%; H 6.64%; N 15.68%.

6.38 g. of 1-methyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidinium methyl sulfate are dissolved in 50 ml. of water. The solution is neutralized with solid potassium carbonate and thus 1-methyl-3-carbamoyl-9a-hydroxy-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)-pyrimidine is obtained which is transferred under discharge of water to 1-methyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine which is precipitated in crystalline form. The yellow crystals are filtered, covered with water and dried. 3.9 g. (94%) of yellow substance is obtained. After recrystallization the melting point of the obtained 1-methyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimide is 241°-242° C.

Analysis: calculated: C 57.96%; H 6.32%; N 20.28%. found: C 58.09%; H 6.27%; N 20.25%.

0.89 g. (4 mmoles) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine are dissolved in 10 ml. of chloroform and 0.62 ml (4.4 mmoles) of chloroformic acid ethyl ester is added dropwise to the mixture under stirring. After stirring for ten minutes a solution of 0.70 g. (4.2 mmoles) of glycine tertiary butyl ester hydrochloride and 0.58 ml (4.2 mmole) of triethylamine in 10 ml. of chloroform are added maintaining the temperature during the addition and for an hour after the addition at -5° to -10° C. The reaction mixture is allowed to stand overnight in the refrigerator, washed three times with 5% sodium bicarbonate and three times with water, dried over sodium sulfate and dried. The residual dark yellow resinuous product is dissolved in the mixture of 5 ml. of ethyl acetate: pyridine:glacial acetic acid: water=240:20:6:11 and the solution is subjected to chromatography on a Kieselgel 60 column of size 50 cm, diameter: 1.8 cm. and of a particle size 0.063-0.125. Eluent solvent: ethyl acetate:pyridine; glacial acetic acid:water=240:20:6:11, flow rate: 30 ml. per hour. The solvent, which is passed through the column is evaporated in vacuo and after evaporation in vacuo the residue is held for a while in vacuo of 10 -2 Hgmm, to remove the pyridine acetate of the solvent. 1.00 g. of colored amorphous resinous substance is obtained, which is dissolved in 10 ml. of ethyl acetate and while still warm, 15 ml. of cyclohexane is added. The precipitated crystals are filtered and air-dried, the following day. 1.8 g. (60%) of 1,6-dimethyl-3-[(N-tert.butoxycarbonyl-methyl)-carbamoyl]-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine of a melting point 180°-182° C. is obtained.

Analysis: calculated: C 60.88%; H 7.51%; N 12.53%. found: C 61.12% H 7.70%; N 11.94%.

4.4 g. (0.02 moles) of 1.6 dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2)pyrimidine and 3.1 ml. (0.022 mole) of triethylamine are dissolved in 50 ml of chloroform and the resulting solution is cooled to -10° C. 2.1 ml (0.022 mole) of chlorormic acid ethyl ester is added dropwise to the solution. After stirring for a further ten minutes a solution of 1.95 g. (0.022 mole) of aniline in 25 ml. of chloroform is added to the mixture, and the temperature is maintained during the addition and after the addition for an hour at -5° C. to -10° C. The reaction mixture is allowed to stand overnight in a refrigerator and the mixture is then shaken out 3 times with a 5% solution of sodium bicarbonate and then 3 times with water. The chloroform solution is dried over sodium sulfate and evaporate in vacuo. 5.7 g. (96%) of yellow crystals of a melting point of 180° C. is obtained. After recrystallization twice from ethanol 1,6-dimethyl-3-(N-phenylcarbamoyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained, melting point: 189°-190° C.

Analysis: calculated: C 68.67%; H 6.44%; N 14.13%. found: C 68.60%; H 6.50%; N 14.21%.

4.4 g. (0.02 moles) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine and 3.1 ml. (0.022 mole) of triethylamine are dissolved in 50 ml. of chloroform. The solution is cooled to -10° C. and 2.1 ml. (0.022 mole) of chloroformic acid ethyl ester is added to the solution, whereafter 1.5 g. (0.022 mole) of methylamine hydrochloride suspended in 25.0 ml. of chloroform and 3.1 ml. of triethylamine are also added. The solution is stirred for 1 hour at a temperature of -5° C. to -10° C. an the mixture is then allowed to stand overnight in a refrigerator. The reaction mixture is then shaken out the following day 3 times with 50 ml. of a 5% aqueous solution of sodium carbonate and then with 50 ml. of water. The chloroform solution is dried over sodium sulfate and evaporated. 3.9 g. (83%) of yellow product is obtained. After recrystallization from ethanol 1,6-dimethyl-3-(N-methyl-carbamoyl)-4-oxo-1,6,7,8,-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained, melting point: 172°-174° C.

Analysis: calculated: C 61.26%; H 7.28%; N 17.86%. found: C 61.08%; H 7.40% N 17.75%.

4.4 g. (0.02 mole) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine and 3.1 ml. of triethylamine are dissolved in 50 ml. of chloroform and 2.1 ml. (0.022 mole) of chloroformic acid ethyl ester and 1.9 g. (0.022 mole) of piperidine dissolved in 25 ml. of chloroform are added dropwise at -10° C. to the solution. The reaction mixture is stirred for a further hour at -5° C. to -10° C. and it is allowed to stand overnight in a refrigerator.

The following day the chloroform solution is three times shaken out with 50 ml. of a 5% solution of sodium bicarbonate and dried over sodium sulfate, and evaporated. 5.2 g. (90%) of 1,6-dimethyl-4-oxo-3-(piperidyl-carbonyl)-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained in the form of yellow incrystallizable oil.

Analysis: calculated: C 66.41%; H 8.01%; N 14.52%. found: C 66.58%; H 8.20%; N 14.47%.

4.44 g. (0.02 mole) of 1.6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine and 3.1 ml. of triethylamine are dissolved in 50 ml. of chloroform and 2.1 ml. (0.022 mole) of chloroformic acid ethyl ester and 5.26 g. (0.022 mole) of diphenylpropylamine dissolved in 25 ml. of chloroform are added dropwise at -10° C. to the solution. The reaction mixture is then stirred for 1 hour at a temperature of -5° C. to -10° C. and the mixture is then allowed to stand overnight in a refrigerator. The following day the chloroform solution is shaken out with a 5% sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated. 6.8 g. (82%) of yellow crystals are obtained. After recrystallization from ethanol 1,6-dimethyl-3-[N-(3,3-diphenyl-propyl)-carbamoyl]-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine of a melting point of 173°-175° C. is obtained.

Analysis: calculated: C 75.15%; H 7.04%; N 10.11%. found: C 74.92%; H 6.96%; N 9.84%.

4.44 g. of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine and 3.1 ml. of triethylamine are dissolved in chloroform at -10° C. and 2.1 ml. of chloroformic acid ethyl ester and 1.6 g. of tert. butylamine in chloroform are added to the solution. The reaction mixture is stirred at a temperature of -5°C. to -10° C. and it is allowed to stand overnight in a refrigerator. The following day the chloroform solution is shaken out with a 5% sodium bicarbonate solution and then with water, dried over sodium sulfate, filtered and evaporated. 5.3 g. (95%) of yellow crystals are obtained. After recrystallization from ethanol 1,6-dimethyl-3-(N-tert-butyl-carbamoyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained, melting point: 179°-181° C.

Analysis: calculated: C 64.96%; H 8.36%; N 15.15%. found; C 64.68%; H 8.32%; N 15.42%.

4.44 g. of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine and 3.1 ml. of triethylamine are dissolved in chloroform and 2.1 ml. of chloroformic acid ethyl ester and 2.7 g. of beta-phenylethylamine are added to the solution at -10° C. The reaction mixture is stirred for 1 hour at a temperature of -5° C. to -10° C. and then allowed to stand overnight in a refrigerator. The following day the chloroform solution is shaken out with a 5% solution of sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated. 2.1 g. of yellow crystals are obtained. After recrystallization from ethanol 1,6-dimethyl-3-[N-(2-phenyl-ethyl)-carbamoyl]-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained, melting point: 141°-143° C.

Analysis: Calculated: C 70.13%; H 7.12%; N 12.91%. found: C 69.83%; H 6.96%; N 12.74%.

According to the method described in Example 2 but using (-)-1,6-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidinium-methylsulfate [(α) D 20 =-59°, (c=2, methanol)] as starting material (+)-1,6-dimethyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained, melting point: 171°-173° C. [(α) D 20 =+71°(c=2, methanol)].

Analysis: Calculated: C 59.71%; H 6.83%; N 18.99%. found: C 59.69%; H 6.78%; N 19.04%.

According to the method described in Example 2 but using (+)-1,6-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine methosulfate [(α) D 20 =+58.5°(c =2, methanol)] as starting material (-)-1,6-dimethyl-3-carbamoyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained. [(α) D 20 =-70°, methanol)].

Analysis: calculated: C 59.71% H 6.83%; N 18.99%. found: C 59.85%; H 6.90%; N 18.92%.

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Composition for 5000 capsules:

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(a.) 3-carbamoyl-1,6-dimethyl-4-oxo-1,6,7,8-

500 g

tetrahydro-4H-pyrido(1,2a)-pyri-

midine(CH-105)

(b.) Potato starch 115 g

(c.) Gelatine 5 g

(d.) Distilled water 30 g

(e.) 2 N hydrochloric acid 5 g

(f.) Ethylalcohol(90%) 60 g

(g.) Potato starch 25 g

(h.) Talc 25 g

(i.) Stearic acid 5 g

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Method

The powder mixture of components (a.) and (b.) is moistened with the solution of components (c.)-(f.) in a suitable kneading-mixing machine, thereafter it is granulated through a 0.3 mm mesh screen and dried at 40° C. The granules thus obtained are regranulated through a 0.15 mm mesh screen. It is admixed with the homogeneous powder mixture of components (g.)-(i.) and filled into hard gelatine capsules in a suitable filling machine. Weight of a capsule: 0.133 g. The finished capsules are packed in a conventional manner.

Composition for 5000 tablets

See Example 14.

Method

The granules prepared according to Example 14 are pressed into tablets in a suitable tabletting machine, weight of a tablet: 0.133 g. The finished tablets are per se furnished with a film coating, or they are formed into dragee with a sugar layer.

0.4 g tablets of coated pills of prolonged effect.

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Composition for 1000 tablets.

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CH-105 active ingredient 400 g

Crystalline cellulose 160 g

Eudragit lacque 7 g

Potato starch 35 g

Talc 22 g

Magnesium stearate 6 g

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Method

The mixture of the active ingredient and the crystalline cellulose is granulated by the propanol solution of the Eudragit lacque in a conventional manner. The homogeneous powder mixture of potato starch, talc and magnesium stearate is admixed with the dried and regranulated product and is formed into tablets weighing 0.63 g under high pressure. The tablets thus obtained may be furnished with film- or sugar layer in a manner known per se.

50 mg injection

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Composition for 10,000 ampules

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CH-105 500 g

Sodium chloride 17 g

Sodium pyrosulphite 3 g

Filled up to 10,000 cm.sup.3 with distilled water

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Method

In a container suitable for injection purposes the solution corresponding to the above composition is prepared in a manner known per se. The nearly isotonic and isohydric solution is filled into ampoules of 1.1 cm 3 under nitrogen. The sterilization is performed for 30 minutes at 120° C.

0.15 g suppository

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Composition for 1000 suppositories

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CH-105 150 g

Suppository mass 2.350 g

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Method

The molten suppository mass is dried over about 60 g of anhydrous sodium sulphate. The active ingredient is homogenized with the filtered suppository mass until warm. The suppositories are formed in a suitable machine, and are packed in a conventional manner. As the suppository mass cocoa-butter or synthetic base substances may be used.

2% ointment

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Composition for 1000 g of ointment

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CH-105 20 g

Methyl cellulose 50 g

Glycerol 100 g

Methyl--p-hydroxy-benzoate

0;5 g

Propyl--p-hydroxy-benzoate

0;3 g

Essence of perfume quantum satis

Distilled water for supplementing

the mixture to 1000 g.

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Method

The methyl- and propyl-p-hydroxy-benzoates are dissolved in glycerol. Homogenized with swelled methyl cellulose the active ingredient and the essence of perfume are dissolved. The finished product is made up with water to 1000 g, and filled into hermethic containers in a conventional manner.

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Composition for 1000 combination suppositories

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CH-105 75 g

Diethyl barbituric acid 15 g

Routine 20 g

Nicotinic amide 25 g

Witepsol-H mass 1.865 g

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Method

The active ingredient is homogenized with diethyl barbituric acid in a kneading-mixing machine. The routine and the nicotinic amide are homogenized with the mass, thereafter it is homogenized with small portions of the suppository mass, dried over anhydrous sodium sulphate in the melt. The suppositories weighing 2 g are formed in a suitable machine.

Tablet, coated pill, dragees

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Composition for 1000 tablets, coated pills, dragees

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CH-105 50 g

Indomethacine 10 g

Crystalline cellulose 35 g

Polivinylpyrrolidone 5 g

Colloidal silicic acid 3 g

Talc 2 g

Magnesium stearate 2 g

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Method

The active inredient and indomethacine are mixed with crystalline cellulose and polyvinylpyrrolidone and passed through a 0.15 mm mesh screen. After mixing with a fine powder mixture of colloidal silicic acid, talc and magnesium stearate the product is directly pressed into tablets weighing 0.107 g.

Remarks

According to the above examples, other active substances e.g. alkaloid-type analgesics, dionine, codeine may be made finished into tablets in a similar way in combination with CH-105.